Fas is a widely expressed surface molecule that induces programmed cell death. While apoptosis mediated by Fas is likely important to development and homeostasis in many organs, its impact is particularly prevalent in the immune system. During normal lymphocyte development it is imperative that self-reactive T and B cells be eliminated. Fas is central to the removal of lymphocytes in peripheral lymphoid tissues. In the absence of Fas, as in the autoimmune Ipr (lymphoproliferative) mouse, autoreactive lymphocytes accumulate in vast numbers. Clearly understanding the signal pathways that are used by Fas or influence Fas are central to normal immune function. While we have established that activation of the MAP kinase, ERK, inhibits Fas-induced apoptosis and also associates with the cytoplasmic tail of Fas, Fas itself does not activate ERK. The purpose of this 10 mth sabbatical study with Dr. Jurg Tschopp is to establish the influence of ERK upon Fas-mediated cell death. The first aim will determine whether the ERK that associates with Fas is preferentially active or inactive. The second aim will continue preliminary studies suggesting ERK may be the kinase that phosphorylates Fas and its adaptor molecule, FADD. The third aim explores whether expression of tillahe cytoplasmic tail of Fas alone will associate with ERK and influence apoptosis by endogenous cell surface Fas. Finally, the curious feature that Fas can actually costimulate the proliferation of resting T cells with CD3 ligation will be studied to determine whether this involves the caspace cascade or whether this involves associated kinases. These studies are logical extensions of ongoing work in my laboratory, but will expose me to new areas of molecular biology and signal transduction.